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Inhibition of human eosinophil chemotaxis and of the IgE-dependent stimulation of human blood platelets by cetirizine.

De Vos C, Joseph M, Leprevost C, Vorng H, Tomassini M, Capron M, Capron A.

Centre d'Immunologie et de Biologie Parasitaire, Unite mixte INSERM 167-CNRS 624-Institut Pasteur, Lille, France.

Cetirizine is a new anti-allergic compound with a potent, long-acting, and specific antihistaminic property. Strongly active in the therapy of urticaria and seasonal or perennial rhinitis, it has been shown to inhibit the in vivo eosinophil attraction at skin sites challenged with allergen in atopic patients. In the present work, we confirmed that, at a therapeutical concentration, this molecule had a potent inhibitory action in vitro on eosinophil chemotaxis induced either by N-formyl-Met-Leu-Phe or platelet-activating factor and also on the IgE-dependent stimulation of platelets. These observations appear in favour of a possible role for cetirizine in the modulation of inflammatory cell interactions in allergic processes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2523357&dopt=Abstract cetirizine Zyrtec



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In vitro inhibition of human liver drug metabolizing enzymes by second generation antihistamines.

Nicolas JM, Whomsley R, Collart P, Roba J.

Department of Product Safety and Metabolism, UCB S.A. Pharma Sector, Braine, l'Alleud, Belgium. jean-marie.nicolas ucb-group.com

Cetirizine, terfenadine, loratadine, astemizole and mizolastine were compared for their ability to inhibit marker activities for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and for some glucuronidation isoenzymes in human liver microsomes. The most pronounced effects were observed with terfenadine, astemizole and loratadine which inhibited CYP3A4-mediated testosterone 6beta-hydroxylation (IC50 of 23, 21 and 32 microM, respectively) and CYP2D6-mediated dextromethorphan O-demethylation (IC50 of 18, 36 and 15 microM, respectively). In addition, loratadine markedly inhibited the CYP2C19 marker activity, (S)-mephenytoin 4-hydroxylation (Ki of 0.17 microM). Furthermore, loratadine activated the CYP2C9-catalyzed tolbutamide hydroxylation (ca. 3-fold increase at 30 microM) and inhibited some glucuronidation enzymes. Mizolastine appeared to be a relatively weak and unspecific inhibitor of CYP2E1, CYP2C9, CYP2D6 and CYP3A4 (IC50Ss in the 100 micromolar range). Cetirizine demonstrated no effect on the investigated activities. A comparison of the inhibitory potencies of cetirizine, terfenadine, loratidine, astemizole and mizolastine with their corresponding plasma concentrations in humans suggests that these antihistamines are not likely to interfere with the metabolic clearance of coadministered drugs, with the exception of loratidine, which appears to inhibit CYP2C19 with sufficient potency to warrant additional investigation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10597902&dopt=Abstract cetirizine Zyrtec



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The pharmacokinetics and pharmacodynamics of hydroxyzine in patients with primary biliary cirrhosis.

Simons FE, Watson WT, Chen XY, Minuk GY, Simons KJ.

Health Sciences Clinical Research Centre, Faculty of Medicine, University of Manitoba, Canada.

Hydroxyzine, a potent H1-receptor antagonist often used for relief of pruritus in patients with hepatic dysfunction, was studied in eight patients, mean age 53.4 +/- SD 11.2 years, with primary biliary cirrhosis. The patients ingested a single dose of hydroxyzine, 0.7 mg/kg (mean dose 43.9 +/- 6.6 mg). Before the dose, then hourly for 6 hours, every 2 hours from 6-12 hours, at 24 hours, and every 24 hours for 6 days, serum hydroxyzine and cetirizine were measured and an intradermal injection of 0.01 mL of a 0.1 mg/mL solution of histamine phosphate was performed. Wheals and flares were traced at 10 minutes and the areas were calculated. Mean peak hydroxyzine levels of 116.5 +/- 60.6 ng/mL occurred at 2.3 +/- 0.7 hours and mean peak cetirizine levels of 500.4 +/- 302.0 ng/mL occurred at 4.8 +/- 2.8 hours. The mean serum elimination half-life of hydroxyzine was 36.6 +/- 13.1 hours, and the mean serum elimination half-life of cetirizine was 25.0 +/- 8.2 hours. The mean hydroxyzine clearance rate was 8.65 +/- 7.46 mL/min/kg, and the mean volume of distribution was 22.7 +/- 13.3 L/kg. The mean wheal area was suppressed (P less than 0.01) from 1 to 120 hours, with maximal suppression from 2 to 48 hours. The mean flare area was suppressed from 1 to 144 hours, with maximal suppression from 3 to 24 hours (P less than 0.01). All patients became sleepy from 0.5 to 6 hours. Blurred vision, dizziness and dry mouth each occurred in two patients. Hydroxyzine elimination is impaired in patients with primary biliary cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2572611&dopt=Abstract cetirizine Zyrtec



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In vitro effects of cetirizine and histamine on human neutrophil function.

Van Epps DE, Kutvirt SG, Potter JW.

Department of Medicine, University of New Mexico, Albuquerque.

IgE-mediated hypersensitivity reactions are characterized by an immediate or early-phase response within the first 30 minutes of exposure to allergen, followed by a late-phase response that begins two to six hours later. Histamine is released during both the early- and late-phase responses and inhibits a variety of neutrophil functions, including superoxide anion generation, chemotaxis, and enzyme secretion. There is some debate as to whether histamine's action on neutrophils is mediated through H1 or H2 receptors, or through a single receptor that recognizes both H1 and H2 agonists. In an effort to understand the mechanism of action of the H1-antagonist cetirizine, we studied its effects on a variety of neutrophil functions. We found that at concentrations up to 35 micrograms/mL), it does not affect superoxide anion production or degranulation. However, at higher concentrations (greater than 35 micrograms/mL), a concentration-dependent inhibition of superoxide anion production is observed. This inhibition is most apparent with responses stimulated by chemotactic factors. Limited inhibition of degranulation and chemotaxis is also seen at high concentrations, but at a level far below that seen with superoxide anion production. These studies indicate that neutrophil function is not altered by the circulating concentrations of cetirizine attained during therapy (less than 10 micrograms/mL), but may be suppressed at higher concentrations. Additional effects of cetirizine on neutrophil function, possible influences of the drug on the inflammatory response, and histamine's modulation of neutrophil function are discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2892444&dopt=Abstract cetirizine Zyrtec



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The comparative pharmacokinetics of H1-receptor antagonists.

Simons FE, Simons KJ, Chung M, Yeh J.

University of Manitoba, Winnipeg, Canada.

H1-receptor antagonists appear to be absorbed rapidly after oral administration, with peak serum concentrations being reached one to three hours after a dose. For most of these drugs, the absolute bioavailability is unknown because no intravenous formulations are available for comparative purposes. The serum elimination half-life values of these agents are variable: a few hours for terfenadine and triprolidine; about 9 hours for cetirizine, azatadine, and loratadine; from 20 to 25 hours for hydroxyzine, chlorpheniramine, and brompheniramine; and from 5 to 14 days for astemizole. Few pharmacokinetic studies of H1-receptor antagonists in children have been reported. However, it is known that chlorpheniramine, hydroxyzine, cetirizine, and terfenadine have shorter elimination half-life values in children than in adults. Regardless of the age of patients, for most of the H1-receptor antagonists the apparent volumes of distribution and total body clearances appear to be large (3.4 to 18.5 L/kg and 4.4 to 32.1 mL/min/kg, respectively). Cetirizine is an exception, with values of 0.8 L/kg and 0.5 mL/min/kg. Urinary excretion of unchanged antihistamine is higher after cetirizine (60% of dose) than any other H1 blocker. For H1-receptor antagonists with long half-life values, steady state may not be reached for several days (chlorpheniramine and brompheniramine) or several weeks (astemizole), and significant accumulation of drug occurs if the dosing interval is more frequent than every half-life. There is no evidence for the introduction of metabolism of H1-receptor antagonists, even after months of treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2892445&dopt=Abstract cetirizine Zyrtec



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Pharmacokinetics of cetirizine in the elderly and patients with renal insufficiency.

Matzke GR, Yeh J, Awni WM, Halstenson CE, Chung M.

Drug Evaluation Unit, Hennepin County Medical Center, Minneapolis, Minnesota.

The disposition of cetirizine, a new H1-receptor antagonist, was evaluated in 30 healthy adults of various ages and in 15 adults with various degrees of renal insufficiency. The purpose of the evaluation was to determine whether dosage schedules of cetirizine will require modification in the elderly or patients with renal insufficiency. We found that the elimination half-life of cetirizine was prolonged in patients with mild and moderate renal insufficiency, compared with age-matched individuals with normal renal function (19.0 +/- 3.3 and 20.9 +/- 4.4 hours, vs 7.4 +/- 3.0 hours, respectively). However, the mean apparent steady-state volume of distribution did not differ significantly between these subject groups (range 0.41 to 0.47 L/kg). Total body clearance and renal clearance of the drug were both significantly lower in the patients with renal insufficiency. In elderly subjects, the elimination half-life of cetirizine was significantly prolonged compared with younger adults, and apparent total body clearance was significantly reduced. Again, there was no significant difference in the volume of distribution between the groups. Linear regression showed good correlations between the disposition characteristics of cetirizine and age as well as creatinine clearance. However, we found no relationship between age and the ratio of apparent total body clearance of cetirizine to creatinine clearance. Thus the disposition of cetirizine is independent of age but dependent on renal function. The relationship between apparent total body clearance of cetirizine and creatinine clearance was significant only in patients with creatinine clearances greater than 40 mL/min. Progressive decrements in creatinine clearance were not associated with similar changes in the pharmacokinetic parameters of cetirizine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2892446&dopt=Abstract cetirizine Zyrtec